P0311 - Esophageal Eosinophil Count Does Not Correlate With the Endoscopic Reference Score Remodeling Subscore in Placebo-Treated Eosinophilic Esophagitis Patients in the Phase 2 Proof-of-Concept and Phase 3 TREET Studies

Sunday, October 24, 2021

3:30 PM – 7:00 PM PT

Location: Shoreline Exhibit Hall

Has Audio

Presenting Author(s)

Ikuo Hirano, MD

Northwestern University Feinberg School of Medicine
Chicago, IL, United States

Ikuo Hirano, MD¹, Marc Rothenberg, MD, PhD², Jonathan M. Spergel, MD³, Seema Aceves, MD⁴, Matthew Greenhawt, MD⁵, Alain M. Schoepfer, MD⁶, Zhen Chen, PhD⁷, Benjamin Ortiz, MD⁷, Angela Khodzhayev, ⁷, Yamo Deniz, MD⁷, Paul J. Rowe, MD⁸, Ledia Goga, PhD⁹, Juby A. Jacob-Nara, MD, MPH, DHSc⁸
¹Northwestern University Feinberg School of Medicine, Chicago, IL; ²Cincinnati Children’s Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH; ³Children's Hospital of Philadelphia, Philadelphia, PA; ⁴University of California, San Diego, CA; ⁵Children’s Hospital Colorado, Aurora, CO; ⁶Lausanne University Hospital, Lausanne, Vaud, Switzerland; ⁷Regeneron Pharmaceuticals, Inc., Tarrytown, NY; ⁸Sanofi, Bridgewater, NJ; ⁹Sanofi, Cambridge, MA

Introduction: Eosinophilic esophagitis (EoE) is a chronic type 2 inflammatory disease of the esophagus. Although eosinophils (eos) are the hallmark of EoE diagnosis, their exact role in disease is unclear. The EoE-Endoscopic Reference Score (EREFS) assesses severity of endoscopically identified inflammatory (edema, exudate, furrows) and remodeling (rings, strictures) aspects of disease activity. To examine the relationship between eosinophilic inflammation and endoscopic disease activity, correlations were assessed between esophageal intraepithelial eos count (eos/high-power field [hpf]) and EREFS in EoE patients (pts) receiving placebo (PBO) in two clinical trials: the 12-week phase 2 proof-of-concept study (POC; NCT02379052) in adults and the 24-week Part A of the 3-part, phase 3 TREET study (P3PA; NCT03633617), in adolescents and adults.

Methods: Endoscopies of the proximal and distal esophagus were performed at baseline (BL) and end of treatment (EOT) and scored for inflammatory and remodeling subscores, and total score using EREFS (higher scores indicate greater severity). Eos/hpf was measured from pinch biopsies of proximal, mid, and distal esophagus at BL and EOT. Pearson correlations were performed between eos/hpf and EREFS total, subscores, and components at BL, EOT, and change from BL at EOT.

Results: Few strong correlations (correlation coefficient > 0.5) were observed at BL between eos/hpf and EREFS in pts receiving PBO of both studies (Table). Moderate-to-strong correlations were observed between EREFS total score and eos/hpf in P3PA, but not POC. Moderate-to-strong correlations were observed in both studies between eos/hpf and the EREFS inflammation subscore and inflammatory components of edema, exudates, and furrows (some of which reached statistical significance). All correlations of eosinophil levels to the EREFS remodeling subscore and rings/stricture components were weak-to-moderate and not statistically significant (P values ranged from 0.07 to 0.94).

Discussion: In these EoE pts, no strong correlations were observed between eos/hpf and endoscopic remodeling as assessed by EREFS. Moderate to strong correlations were observed between eos/hpf and endoscopic markers of inflammation. Combined with histology, endoscopic assessment of remodeling aspects of EoE provides a more comprehensive characterization of disease activity. Further study, with larger sample sizes, is required to verify and validate these findings in other populations, duration of observation, and treatment contexts.

Table. Correlations between esophageal intraepithelial eosinophil count (eos/hpf) and EREFS total score, inflammation and remodeling subscores, and individual components scores in patients with EoE receiving placebo in the phase 2 POC study and part A of the phase 3 LIBERTY TREET study.
Pearson correlation coefficients (ρ)	EoE Phase 2 POC study (N = 24)			EoE Phase 3 TREET Part A study (N = 39)
Pearson correlation coefficients (ρ)	Baseline (n = 24)	EOT Week 12 (n = 22)	Change from BL to EOT (n = 22)	Baseline (n = 39)	EOT Week 24 (n = 27)	Change from BL to EOT (n = 27)
Eos/hpf x EREFS total^a ρ P value	0.3472 0.0969	0.2854 0.2007	0.3382 0.1249	0.5625 0.0001	0.4677 0.0130	0.0422 0.8362
Eos/hpf x EREFS inflammation subscore^b ρ P value	0.3591 0.0850	0.4858 0.0207	0.4532 0.0331	0.5482 0.0002	0.3627 0.0626	0.1128 0.5790
Eos/hpf x EREFS edema component ρ P value	0.3431 0.1013	0.3522 0.1088	0.4100 0.0576	0.2922 0.0710	−0.0635 0.7555	0.0111 0.9567
Eos/hpf x EREFS exudates component ρ P value	0.3075 0.1453	0.5195 0.0121	0.4412 0.0390	0.4735 0.0020	0.3987 0.0387	0.2695 0.1758
Eos/hpf x EREFS furrows component ρ P value	0.1981 0.3576	0.1688 0.4575	0.2415 0.2829	0.3803 0.0163	0.3807 0.0496	−0.0798 0.6952
Eos/hpf x EREFS remodeling subscore^c ρ P value	0.1686 0.4353	−0.0249 0.9136	0.0165 0.9428	0.0724 0.6634	0.2286 0.2542	−0.1276 0.5297
Eos/hpf x EREFS rings component ρ P value	0.0931 0.6687	0.0593 0.7958	−0.1622 0.4758	0.0480 0.7730	0.2408 0.2289	−0.1419 0.4841
Eos/hpf x EREFS stricture component ρ P value	0.2230 0.2986	−0.1644 0.4695	0.3958 0.0680	0.1052 0.5265	0.0303 0.8818	0.0310 0.8794

^aEREFS total score is the sum of all component scores for proximal and distal regions.

^bEREFS inflammation subscore is the sum of edema, exudates, and furrows for proximal and distal regions.

^cEREFS remodeling subscore is the sum of rings and strictures for proximal and distal regions.

Cohen’s rule of thumb denotes a correlation coefficient of 0.10 as weak relationship, 0.3 as moderate relationship, and 0.5 as strong relationship (Cohen J.,1988, Statistical Power Analysis for the Behavioral Sciences, 2nd ed. Hillsdale, NJ: Erlbaum).

Analyses were performed post hoc and P values are nominal.

BL, baseline; EREFS, Endoscopic Reference Score; Eos, eosinophils; EOT, end of treatment; hpf, high-powered field.

Disclosures:

Ikuo Hirano: Adare Pharma Solutions – Consultant, Grant/Research Support. Allakos – Consultant, Grant/Research Support. AstraZeneca – Consultant, Grant/Research Support. Calyx – Consultant. Elodi – Consultant, Grant/Research Support. Esocap – Consultant. Gossamer Bio – Consultant. Lilly – Consultant. Meritage – Grant/Research Support. Receptos/BMS – Consultant, Grant/Research Support. Regeneron Pharmaceuticals, Inc. – Consultant, Grant/Research Support. Shire/Takeda – Consultant, Grant/Research Support.

Marc Rothenberg: Allakos – Consultant. AstraZeneca – Consultant. BMS – Consultant. Cincinnati Children’s Hospital – Other Financial or Material Support, royalties; inventor of patents owned by Cincinnati Children’s Hospital. ClostraBio – Consultant, Stockholder/Ownership Interest (excluding diversified mutual funds). Mapi Research Trust – Other Financial or Material Support, royalties from PEESSv2. PulmOne – Consultant, Stockholder/Ownership Interest (excluding diversified mutual funds). Spoon Guru – Consultant, Stockholder/Ownership Interest (excluding diversified mutual funds). Teva Pharmaceuticals – Other Financial or Material Support, royalties from reslizumab. UpToDate – Other Financial or Material Support, royalties.

Jonathan M. Spergel: Allakos – Consultant. DBV Technologies – Consultant, Grant/Research Support. Novartis – Consultant. Regeneron Pharmaceuticals, Inc. – Consultant, Grant/Research Support. Shire/Takeda – Consultant.

Seema Aceves: Aimmune Therapeutics – Consultant. AstraZeneca – Consultant. UCSD patent, Shire-Takeda licensed – Other Financial or Material Support, Co-inventor of oral viscous budesonide (UCSD patent, Shire-Takeda licensed)..

Matthew Greenhawt: Allergenis – Advisory Committee/Board Member. Allergy Practice Parameters – Other Financial or Material Support, joint task force. Allergy Therapeutics – Advisory Committee/Board Member. Aquestive – Consultant. Aravax – Advisory Committee/Board Member. DBV Technologies – Advisory Committee/Board Member. Genentech – Advisory Committee/Board Member. ImSci – Other Financial or Material Support, honorarium. MedLearningGroup – Other Financial or Material Support, honorarium. National Peanut Board – Advisory Committee/Board Member. Novartis – Advisory Committee/Board Member. Nutricia – Advisory Committee/Board Member. Pfizer – Advisory Committee/Board Member. Prota – Advisory Committee/Board Member. Regeneron Pharmaceuticals, Inc. – Advisory Committee/Board Member. Sanofi – Advisory Committee/Board Member. US World Meds – Advisory Committee/Board Member.

Alain M. Schoepfer: Adare Pharma Solutions – Consultant. Aptalis – Consultant, Grant/Research Support. AstraZeneca – Grant/Research Support. Dr Falk – Consultant, Grant/Research Support. GSK – Grant/Research Support. Nestlé – Grant/Research Support. Novartis – Grant/Research Support. Receptos/BMS – Grant/Research Support. Regeneron Pharmaceuticals, Inc. – Grant/Research Support.

Zhen Chen: Regeneron Pharmaceuticals, Inc. – Employee, Stockholder/Ownership Interest (excluding diversified mutual funds).

Benjamin Ortiz: Regeneron Pharmaceuticals, Inc. – Employee, Stockholder/Ownership Interest (excluding diversified mutual funds).

Angela Khodzhayev: Regeneron Pharmaceuticals, Inc. – Employee, Stockholder/Ownership Interest (excluding diversified mutual funds).

Yamo Deniz: Regeneron Pharmaceuticals, Inc. – Employee, Stockholder/Ownership Interest (excluding diversified mutual funds).

Paul J. Rowe: Sanofi – Employee, Stockholder/Ownership Interest (excluding diversified mutual funds).

Ledia Goga: Sanofi – Employee, Stockholder/Ownership Interest (excluding diversified mutual funds).

Juby Jacob-Nara: Sanofi – Employee, Stockholder/Ownership Interest (excluding diversified mutual funds).